Urothelial carcinoma is a relatively common cancer with a significant risk of disease progression and spread. Untreated disease-free survival rates are quite low, generally below 5%. The application of M-VAC chemotherapy (methotrexate, vinblastine, adriamycin and cisplatin) is currently considered standard of care, resulting in response rates of over 50%, median survival of > 1 year, and 3-year survival of 20-25%, for inoperable or metastatic cases. The M-VAC regimen has been shown to be superior to the CISCA regimen as well as cisplatin alone. However, it is a markedly toxic treatment with neutropenic sepsis rates as high as 10% and treatment-related mortality on the order of 3-4%. Increases in efficacy might be achieved through the addition of novel chemotherapy agents (ie: navelbine, gemcitabine) to M-VAC or through dose-intensification of standard M-VAC. Conversely, toxicity might be reduced via the administration of concurrent growth factors (ie: G-CSF).
Two studies have reported on the use of docetaxel and cisplatin (DC) chemotherapy in advanced urothelial carcinoma and found response rates of 52-60%, median survival of 8-13.6 months, and grade 3/4 hematologic toxicity rates as low as 33% (Sengelov et al, 1998; Dimopoulos et al, 1999). The purpose of this randomized phase III trial was to compare M-VAC + G-CSF to DC + G-CSF in patients with advanced urothelial carcinoma.

On multivariate analysis, performance status and visceral metastases were independent prognostic factors. When these factors were adjusted for, OS benefit lost statistical significance, but TTP remained significant.

M-VAC is superior to DC as first line therapy in advanced urothelial malignancy.

Only time-to-progression showed statistically significant improvement in M-VAC group on multivariate analysis.

Overall survival effect was likely a result of the performance status imbalance between the treatment arms.

Use of G-CSF appeared to reduce toxicity of both chemotherapy regimens.

M-VAC with G-CSF support should be considered the standard of care for inoperable or metastatic urothelial carcinoma.

Clinical/Scientific Implications

The current standard of care in advanced stage bladder carcinoma patients is M-VAC chemotherapy. The results of this study show a longer time-to-progression of disease with M-VAC as compared to a combination docetaxel-cisplatin regimen, further establishing the value of M-VAC. Although the authors did not demonstrate overall survival benefit on multivariate analysis, the smaller number of patients in this analysis likely lacked statitical power to detect a survival benefit. The data from this trial are consistent with 2 other studies (von der Maan et al and Sternberg et al) using M-VAC in advanced urothelial cancer; median survival rates, time-to-progression and response rates in those two studies are all comparable to those seen here. However, less toxicity was seen in this trial, and the authors attribute this to the use of G-CSF. However, whether or not this mandates a change in management standards to incorporate G-CSF to all M-VAC regimens in advanced cases remains to be seen. What is known is that there is certainly room for improvement in the side effect profile of this efficacious chemotherapy regimen, and G-CSF may very well be one answer.